The discovery of the antibiotic properties of penicillin and the application of the discovery is one of the most confusing, as well as one of the most important, in the history of biochemistry. But if any one ‘experiment’ can be pinpointed as the moment of discovery, it was when Alexander Fleming noticed something odd in a dirty Petri dish in his laboratory at St Mary’s Hospital, in London, in 1928.
Fleming already had something of a track record of serendipitous discovery. Like many researchers in the years following the First World War (see here), in the early 1920s Fleming was searching for any chemical agent with bacteria-killing properties. The cultures that they studied were grown in Petri dishes – shallow, circular glass dishes. One day in 1922, Fleming had a runny nose, which dripped mucus onto one of these plates. The nasal fluid killed the bacteria, leading him to discover lysozyme, an enzyme present in tears, and which is a natural antibacterial agent. Unfortunately, though, the microbes that are most strongly affected by lysozyme do not infect people.
In September 1928, Fleming returned from a holiday and set about clearing up a jumble of Petri dishes that he had left behind uncleaned. One of them, which had been seeded with staphylococci, contained a spot of mould, with a clear circle around the mould, where the staphylococci had been killed. Fleming grew the mould in culture, identifying it as a member of the genus Penicillium, and finding that it killed a variety of bacteria. It later turned out that a colleague in a lab on the floor below had been working with Penicillium, and it seems that a spore from his lab had blown out of the window and in through the window of Fleming’s lab, both of which were open in the summer heat.
Fleming made an antibacterial broth from the mould, which he initially called ‘mould juice’, before naming it ‘penicillin’ on 7 March 1929. But although he published news of his discovery and carried out some further experiments, Fleming did not pursue the investigation of penicillin, partly because it turned out to be ineffective against typhoid and paratyphoid, the diseases he was working on at the time. It was also very difficult to produce penicillin in quantity. As Fleming later said: ‘When I had some active penicillin I had great difficulty in finding a suitable patient for its trial, and owing to its instability there was generally no supply of penicillin if a suitable case turned up. A few tentative trials gave favourable results but nothing miraculous and I was convinced that before it could be used extensively it would have to be concentrated and some of the crude culture fluid removed.’36
Nevertheless, when a junior colleague of Fleming, Cecil George Paine, moved from St Mary’s to Sheffield in 1929 he took knowledge of the discovery with him. In 1930, he used penicillin to clear up infections in babies at the Sheffield Royal Infirmary, but he did not publish news of this success, and with the same difficulties in producing penicillin in quantity he did not follow up the achievement. His notes were only rediscovered in 1983.
Although Fleming did attempt to interest chemists in developing techniques to produce large quantities of penicillin, no progress was made until 1938, when a team of researchers at the Dunn School of Pathology, in Oxford, had completed a project to crystallize lysozyme. They decided to investigate other natural antibacterial agents, in the mistaken belief that they must all be enzymes, like lysozyme. One of the agents they chose to study was penicillin. They developed a technique for concentrating penicillin, and published their results in The Lancet in August 1940. By then, with the Second World War raging, the immediate importance of the work was recognized, and funding was provided for the research into mass production of the medicine to be stepped up, initially in Britain and then in the United states. By 1944, 2.3 million doses of penicillin were available in time for the D-Day invasion of Normandy. The two key researchers involved at the Dunn School were Howard Florey and Ernst Chain, who shared the Nobel Prize with Fleming in 1945 ‘for the discovery of penicillin and its curative effect in various infectious diseases’.
In a sobering footnote to his Nobel Lecture, Fleming gave a warning which resonates in these days of drug-resistant bacteria: ‘Mr. X. has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci, but enough to educate them to resist penicillin. He then infects his wife. Mrs. X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs. X dies. Who is primarily responsible for Mrs. X’s death? Why Mr. X, whose negligent use of penicillin changed the nature of the microbe.’37
LEFT: © St Mary’s Hospital Medical School/Science Photo Library
Photograph of the original culture plate of the fungus Penicillium notatum, made by the Scottish bacteriologist Alexander Fleming (1881–1955).
RIGHT: © St Mary’s Hospital Medical School/Science Photo Library
A drawing of the original culture plate of the fungus Penicillium notatum, made by Fleming, with his notes.
© National Library of Medicine/Science Photo Library
A Second World War advertisement for penicillin, a new drug that could cure gonorrhoea.